Benzene sulfonyl ureas and process for their preparation



United States Patent Germany No Drawing. Filed July 31, 1956, Ser. No.601,107

Claims priority, application Germany, Oct. 15, 1955,

F 12 Claims. (Cl. 260-553) It is known from literature that certaincompounds belonging to the class of aminobenzene sulphonamides arecapable of lowering the blood sugar value in test animals, for example,of dogs. Thus, for example, paraaminobenzenesulphonamidodsopropyl-thiodiazole produces a moderate lowering of theblood sugar value in dogs for 4 to 6 hours (compare: Jean la Barre andJean Reuse, Arch. nerland. physiol. 28 [1947], p. 475).

There are also known certain benzene-sulphonyl ureas, such asN-benzenesulphonyl-urea, N-benzenesulphonyl- N-phenyl-urea,N-benzenesulfonyl-N:N'-diethyl-urea, N- para-toluene sulphonyl-urea andN-para-toluenesulphonyl- N-phenyl-urea (compare: Chem. Rev., vol. 50,pp. 28/ 29). However, these substances have not yet attained anycommercial importance. Other products belonging to the series ofsulphonyl-ureas are known from US. specification No. 2,390,253 andFrench specification No. 993,465.

The present invention provides benzene sulphonylureas of the generalformula in which R represents hydrogen, chlorine, bromine, and alkyl andalkoxy groups having at most 6 carbon atoms, especially the methyl andmethoxy groups, R represents chlorine and bromine and R represents analkyl-, alkenyl-, cycloalkyland cycloalkylalkyl radical containing 2 to7 or 8 carbon atoms and non-toxic basic salts thereof.

The radical R may be an alkylor alkoxy radical containing 1 to 6 carbonatoms. As alkyl groups are mentioned, for example, methyl, ethyl,propyl, butyl, pentyl or hexyl, especially methyl. The alkyl substituentmay be unbranched or branched, and may be bound in the paraposiiion ofthe phenyl radical or in other positions; in the latter case moreespecially in the meta-position. The radical R may also be a chlorine orbromine atom.

There may also be mentioned dihalogeno phenyl radicals, such asdichloroor dibromo phenyl groups. There may also be mentioned phenylresidues that contain both an alkyl or alkoxy group and a halogen atom,such as a methyl-chlorophenyl group. The substituents may be bound inany desired position to the benzene nucleus.

R may be chlorine or bromine.

The compounds of the above general formula are made by methods known formaking sulphonyl-ureas. As examples the following processes may bementioned:

A benzene-sulphonyl isocyanate substituted by 1 or- 2 halogen atoms orby a halogen atom and an alkyl or alkoxy group in the benzene nucleus,may be reacted with a primary butylamine or another primary alkylamineor an alkenylamine, cyclo-alkylamine or cycloalkylalkylamine containing2 to 7 or 8 carbon atoms. Conversely, the desired sulphonyl-urea can bemade by reacting a butyl isocyanate or other appropriate isocyanate witha benzene-sulphamide substituted by 1 or 2 halogen atoms or by a halogenatom and an alkyl or alkoxy group in the benzene nucleus, advantageouslyin the form of a salt 3,384,757 Patented May 21, 1968 ice thereof.Instead of isocyanates there may be used compounds convertible intoisocyanates in the course of the reaction, such as acid azides, forexample, Valerie acid azide. In another process for making the newcompounds there are used, instead of isocyanates, urethanes; and anydesired carbamic acid ester, such as methyl, ethyl, propyl, butyl oraryl esters, can be used for this purpose. For example, a benzenesulphonyl-urethane substituted by 1 or 2 halogen atoms or by a halogenatom and an alkyl or ,alkoxy group in the benzene nucleus, may bereacted, for example, with butylamine or another primary amine, or,conversely, an alkyl-urethane may be reacted with an appropriatebenzene-sulphamide, advantageously in the form of a salt thereof.Carbamic acid halides can also be used with special advantage. Thus, forexample, the new sulphonyl-ureas are formed by reacting a butylcarbamicacid chloride with a benzene sulphamide substituted by 1 or 2 halogenatoms or by a halogen atom and an alkyl or alkoxy group in the benzenenucleus, or by reacting a correspondingly substituted benzenesulphonyl-carbamic acid chloride with a butylamine or another primaryamine. In a further process a correspondingly substituted benzenesulphonyl-urea, which is unsubstituted or substituted by other radicals,such as acyl and in the NH group, is converted into a benzenesulphonyl-alkyl-urea by reaction with amines of the formula H NR forexample butylation, if desired, with butylamine. Alternatively, analkyl-urea may be reacted with a benzene-sulphamide substituted by 1 or2 halogen atoms or by a halogen atom and an alkyl or alkoxy group in thebenzene nucleons. Instead of the alkyl-ureas there may be used thecorresponding iso-urea ethers, advantageously in the form of theirsalts, and they are reacted with benzene sulphonic acid chlorides, andthe product so obtained is then converted by acid hydrolysis into thedesired sulphonyl-urea. Instead of the alkyl-ureas or the correspondingiso-urea ethers, other derivatives may be used.

In further processes for making the new compounds the correspondingthiourea is first prepared, and sulphur is eliminated therefrom in aconventional manner; or a corresponding N-benzenesulphonyl-N-alkyl-guanidine is prepared in known manner (for example,reacting a benzenesulphonyl-cyanarnide with a butylamine or with anotherprimary amine), and the resulting guanidine is then hydrolysed. In allcases there may be used, instead of butylamine, another primaryalkylamine, or an alkenylamine, cycloalkylamine orcycloalkyl-alkyl-amine. In these reactions the components are always tobe chosen in such a manner that the radical R contained in the reactionproduct contains 2 to 7 or 8 carbon atoms.

As alkyl residues, which may be present as substituents in the phenylradical, and bound, if desired, through an oxygen atom, there may bementioned, more especially, those of low molecular weight. Especiallyadvantageous are those containing 1 carbon atom, but residues containing26 carbon atoms may be present. When these residues are of highermolecular weight the activity of the products is generally considerablylower. The benzenesulphonyl compounds may contain as substituents in thephenyl residue one or two halogen atoms, preferably chlorine or bromineatoms, or a halogen atom and an alkyl or alkoxy group.

The primary amines used as starting materials in the above processesadvantageously contain alkyl-, alkenyl-, cycloalkylor cycloalkylalkylradicals containing 2 to 6 carbon atoms. However, they may also contain7 and 8 carbon atoms, but radicals of higher molecular weight generallyreduce the activity of the products.

The reaction conditions under which the aforesaid processes are carriedout may vary within wide limits and are adapted to each particular case.For example, the reactions may be carried out with the use of solventsat room temperature or at a higher temperature. Particularly suitableare the following processes:

(1) The reaction of a compound of the general formula in which R and Rhave the meanings given above, and

advantageously in the form of a suitable alkali metal salt,

with an isocyanante of the general formula R NCO in the presence of asolvent, for example, nitro'benzene or acetone, at the ordinary or ahigher temperature.

(2) The reaction of a benzene sulphonyl-carbamic acid ester of thegeneral formula in which R and R have the meanings given above, and Rrepresents any desired, preferably lower, hydrocarbon residue, with anequivalent quantity of an amine of the formula R NH In this case it isadvantageous to use as solvent a glycol-monoalkyl ether and to conductthe reaction at a temperature within the range of 100 C. to 140 C. Inthis reaction the ratio of the reactants to solvent may be ofimportance; advantageously the proportion of solvent amounts to 55-65percent of the total quantity of the reaction mixture.

To obtain the products in as pure a state as possible, it isadvantageous to separate the product thorougly from the benzenesulphamide used as starting materials or formed in the course of thereaction. Advantageously, this is carried out taking up the product indilute ammonia (1 part by volume of ammonia to 20-30 parts by volume ofWater), since the sulphamides are generally sparingly soluble in thismedium at room temperature.

Suitable starting materials are: halogen-benzenesulphonyl isocyanates,in which the halogen atom may be in any desired position of the benzenenucleus; correspondingly substituted benzenesulphamides; correspondinglysubstituted benzenesulphonylurethanes containing in the urethanecomponent a lower alkyl radical, for example, a methyl, ethyl, propyl orbutyl group, and more especially an ethyl group, or an aryl radical;correspondingly substituted benzenesulphonyl-ureas; and correspondinglysubstituted benzene sulphonic acid halides.

Furthermore, there may be used as starting materials:dihalogen-benzene-sulphonyl isocyanates, of which the halogen atoms maybe in any desired positions of the benzene nucleus; correspondinglydisubstituted benzene sulphamides; correspondingly disubstitutedbenzene-sulphonylurethanes containing in the urethane component a loweralkyl radical, for example, a methyl, propyl, butyl or especially anethyl group, or an aryl residue; correspondingly disubstitutedbenzene-sulphonyl-ureas; correspondingly disubstituted benzene sulphonicacid halides; and correspondingly disubstituted benzene-sulphonylcarbamic acid halides.

There may also be used as starting materials methylchloro-benzeneandmethoxy-chlorobenzene-sulphonyl derivatives for example, in the form ofthe chlorides, amides, isocyanates, carbamic acid halides, carbamic acidesters or ureas. Instead of the methyl group, an ethyl, propyl, butyl,pentyl or hexyl group may be present.

For the reaction with the compounds mentioned above there may be usedthe following primary amines: As alkylamines there may be mentioned, forexample, ethylamine, n-propylamine, isopropylamine, n-butylamine,isobutylamine, secondary butylamine, tertiary butylamine, pentylamine-(1), pentylamine-(2), pentylarnine-(ES), 3- methylbutylamine-( 1),2-methyl-butylamine-( 1), 2z2-dimetl1yl-propylamine-( 1),3-methyl-butylamine-(2), hexylamines such as hexylamine-(l) andZ-methyl-pentylamine- (1), heptylamines such as heptylamine-(l) andheptylamine-(4), and octylamines such as octylamine-(l).

There may be mentioned as examples of alkenylamines, e.g. allylamine andcrotylamine; as cycloalkylamines, e.g. cyclo-hexylamine andcyclopentylamine; and as cycloalkylalkylamines, e.g.cyclohexyl-methylamine and cyclohexylethylamine.

Instead of using the aforesaid amines, the corresponding isocyanates,urethanes, carbamic acid halides, ureas or isourea ethers (obtainablefrom the aforesaid amines) may be reacted with suitably substitutedbenzene sulphamides or halides.

When the synthesis of the desired sulphonyl-urea starts from acorresponding thiourea, for example, from N4- chloroorN-4-bromo-benzenesulphonyl-N'-alkyl-, alkenyl-, -cycloalkylor-cycloalkylalkylthio-ureas the hydrocarbon radicals containing 2 to 7 or8 carbon atoms, the sulphur may be eliminated with a heavy metal oxideor a salt thereof, for example, an oxide or salt of lead, copper orsilver, in an aqueous or alcoholic solution.

Alternatively, the desired sulphonyl-urea can be prepared by hydrolysingan appropriately constituted quanidine with a dilute acid or alkalinesolution.

As has been demonstrated by experiments on animals and in clinicaltests, the products of the invention produce a substantial lowering ofthe blood sugar level. They may be used as such or in the form of theirsalts, or in the presence of substances that cause salt formation. Forsalt formation there may be used, for example, ammonia, an alkalinesubstance such as an alkali metal or alkaline earth metal hydroxide, analkali metal carbonate or bicarbonate, or a physiologically toleratedorganic base. These salts have the same blood sugar lowering properties.It is assumed that, by the alkaline reaction in the human alimentarytract, the compounds are converted into their salts and are absorbed assuch. The compounds can be made up, inter alia, into preparationssuitable for oral administration and lowering the blood sugar in thetreatment of diabetes.

The preparations suitable 'for oral administration, for example tabletsand drages, can be prepared by homogeneously mixing the followingingredients, granulating them in the moist state, if necessary, anddrying and pressing them.

0.5 gram of a compound of the general formula Q-sm-rvn-oo-mna,

in which R represents hydrogen, chlorine, bromine, alkyl and alkoxygroups containing up to 6 carbon atoms, R represents chlorine andbromine and R represents an alkyl, alkenyl, cycloalkyl andcycloalkyl-alkyl radical containing 2-7 or 8 carbon atoms.

0.1395 gram of wheat or maize starch 0.0075 gram of talcum 0.003 gram ofmagnesium stearate.

A further object of the present invention is therefore: Pharmaceuticalpreparations which contain a compound of the general formula In animaltests the action on the blood sugar level has been demonstrated, forexample, on mice, rats, guinea pigs, rabbits, cats and dogs. When, forinstance, a compound of the invention is administered to normally fedrabbits in a single average dose of 400 mg./kg. in, for example, asolution rendered alkaline with bicarbonate, or in the form of an alkalimetal salt, a lowering of the blood sugar level sets in rapidly andreaches a maximum (about to percent of the initial value) in the courseof about 3 to 4 hours.

The blood sugar level can be measured by hourly analyses by the methodof Hagedorn-Iensen. The lowering of the blood sugar is determined bycomparison with the blood-sugar level of control animals fed in the sameway but not so treated.

The activity of the products of the invention is shown in the followingtable:

urea

The testing of the compounds on dogs has the advantage that theresorption conditions in the alimentary canal are similar to those ofhuman beings, and that the blood sugar level exhibits smaller individualvariations than in rabbits. In the canine tests the administration ofsmall doses even of the free sulphonyl-ureas yields readily reproduciblevalues. When the compound to be tested is administered to a dog, priorto feeding it, in a single dose of mg./kg. and the blood sugar level isdetermined at certain intervals, the reductions in the blood sugar levelshown in the following table are observed:

The above values were determined by comparison with the blood sugarlevels measured on similarly fed, but untreated control animals.

As compared with compounds of similar constitution of the sulphanilylseries the compounds of the present invention are distinguished, on onehand, in that they are more resistant to external oxidising influences,such as atmospheric oxygen, which is of importance to their shelfiifeand handling, and, on the other, in that they have no bacteriostaticaction.

Furthermore, the new compounds do not produce thesecondary effects ofsulphonamides on the blood (Heinz bodies) or on the thyroid gland, northe digestive disturbances caused by action on the bacterial flora ofthe alimentary tract. The folowing examples serve to illustrate theinvention; but they are not intended to limit it thereto:

Example l.N-(4-chloro-benzenesulphonyl)-N'-nbutyl-urea 95.5 grams of4-chlorobenzene-sulphamide are suspended in 500 cc. of acetone anddissolved by addition of a solution of 20 grams of sodium hydroxide in400 cc. of water. The solution is cooled to +10 C., and, while stirringvigorously, 49.5 grams of n-butyl isocyanate are slowly added dropwise.The reaction mixture is stirred until the odour of isocyanate hasdisappeared. It is then filtered with suction, about two thirds of thesolvent are distilled off, the residue is diluted with water andcarefully acidified with acetic acid, while stirring. The precipitate isat first somewhat pasty but becomes crystalline on standing in the cold.The N-(4chloro-benzenesulphonyl)-N-nbutyl-urea, obtained in a goodyield, is purified by being dissolved in dilute ammonia solution. Thesolution is clarified with charcoal and acidified with dilute aceticacid. The precipitated N-(4-chloro-benzenesulphonyl)- N'-n-butyl-urea isfiltered off with suction and thoroughly washed with water on thefilter. After recrystallisation from dilute ethanol the product melts at-116" C.

In an anlogous manner there is obtained from 3-chlorobenzenesulphonamide, N-(3-chloro-benzenesulphonyl)- N'-n-butyl-urea melting at1ll1l2 C.

2.9 grams of sulphonyl-urea are dissolved in 10 cc. of l N-sodiumhydroxide solution. The solution is filtered and evaporated to drynessunder reduced pressure. After drying over phosphorus pentoxide, theresidue is an amorphous white powder which, when dissolved in water,yields a clear solution. There can be prepared aqueous solutions ofdifierent concentrations showing a pH-value of 8-9.

The sodium salt of N-(3 chloro-benzenesulphonyl)- N'-n-butyl-urea has noprecise melting point but deliquesces slowly on heating above 60 C.

Example 2.-N- (4-chloro-benzenesulphonyl) -N'- cyclohexyl-urea 50 gramsof finely ground potassium carbonate are added to a solution of 25 gramsof 4-chlorobenzenesulphamide in 200 cc. of dry acetone, and thesuspension is refluxed for 3 hours. 16.5 grams of cyclohexyl isocyanateare then slowly added dropwise, while stirring, at 50 C. The mixture isfurther stirred at the same temperature until the odour of isocyanate isno longer detected. After being cooled, the mixture is filtered withsuction, the residue is dissolved in water, any undissolved matter isfiltered ofif, and the solution is decolorised with carbon. Thesulphonyl-urea is then precipitated by cautiously adding an acid, thendissolved in dilute ammonia solution, the solution is clarified withcarbon and acidified with acetic acid. A good yield ofN-(4-chloro-benzenesulphonyl)-N'-cyclohexylurea precipicates. It isfiltered off with suction, thoroughly washed on the filter with water,and recrystallised from acetonitrile. It melts at 1S8159 C.

Example 3 .-N- (4-bromo-benzenesulphonyl -N'-nbutyl-urea A solution of 8grams of sodium hydroxide in 75 cc. of water is added to a solution of47 grams of 4-bromobenzene-sulphamide in cc. of acetone. While stirringvigorously, 20 grams of n butyl isocyanate are slowly added dropwise at20 C. to the reaction mixture. When the addition is complete, themixture is stirred until the odour of isocyante has disappeared. Thereaction mixture is then evaporated, and the residue is dissolved inwater. The solution is clarified with carbon and acidified withhydrochloric acid. To purify the precipitated sulphonylurea, it isdissolved in dilute ammonia solution, and the solution is clarified withcarbon and acidified with acetic acid. N-(4-bromo-benzenesulphonyl)-N'-n-butyl-urea is obtained in good yield. It is filtered off withsuction, washed with 'water and recrystallised from dilute ethanol. Itmelts at l26127 C.

Example 4.-N-(4-chlorobenzenesulphonyl) -N-allyl-urea 34 grams ofN-(4-chlorobenzenesulphonyl)-carbamic acid methyl ester melting at 92-93C. (prepared by reacting 4-chloro-benzene-sulphamide with chloroformicacid methyl ester in the presence of anhydrous potassium carbonate) aredissolved in 50 grams of glycol monomethyl ester, 11.5 grams ofallylamine are added to the solution and the reaction mixture is heatedfor 20 hours to 100 C. The residue obtained after distilling off theglycol monomethyl ether is treated with about 300 cc. of dilute ammonia(1:25), any undissolved matter is filtered ofi, the solution isdccolorized with animal charcoal and the sulphonyl-urea is precipitatedby slowly acidifying with 2 N-hydrochloric acid. After filtering withsuction, washing with water and recrystallizing from ethanol of 70percent strength, a good yield of N-(4-chlorobenzenesulphonyl)-N-allyl-urea is obtained wh ch melts at 183-1843C. Instead of glycol monomethyl ether there may also be used as solventshydrocarbons such as xylene, toluene, chlorobenzene.

Example 5.-N-(4-chlorobenzenesulphonyl)- N-cyelohexylmethylau'ea 66grams of 4 (chloro-benzenesulphonyl)-carbarnic acid ethyl ester (meltingpoint 92-93 C.; prepared by reacting 4chlorobenzene-sulphamide withchloroformic acid ethyl ester in the presence of dry pulverizedpotassium carbonate) and 29 grams of cyclohexylmethylamine are heatedfor 16 hours at ll C. in 120 cc. of glycol monomethyl ether. Thereaction mixture is concentrated under reduced pressure, water is addedto the residue while still warm and it is then dissolved by cautiouslyadding a sodium hydroxide solution. The solution is clarified withanimal charcoal and acidified with hydrochloric acid. The precipitate,which separates at first in the form of a smeary mass, soon solidifieswhen digested in the warmth. It is filtered with suction and washed wellWith water. For purification it is dissolved in dilute ammonia, anyundissolved matter is filtered off, the solution is clarified withanimal charcoal and acidified again with hydrochloric acid. TheN-(4-chloro-benzenesulphonyl)-N'- cyclohexylmethyl-urea which separatesin a good yield is filtered off with suction, washed well with waterand, after drying, recrystallized. from acetic acid methyl ester. Theproduct melts at 171 C.

Example 6.-N-(4-chloro-benzenesulphonyl) -N'n-butyl-urea In a roundflask 7.5 grams of n-butylamine are poured over 25 grams ofN-(4-chloro-benzenesulphonyl)-carbamic acid methyl ester. The reactionmixture is heated in an oil bath to about 120-130 C., while the methanolformed during the reaction is distilled off under reduced pressure.After about 1-1 /2 hours the product is allowed to cool and theN-(4-chloro-benzenesulphonyl)-N-butylurea obtained is dissolved indilute alcohol and then reprecipitated. The product melts at 115-116 C.

Example 7.N-(4-methyl-3-chloro-benzenesulphonyl)-N-(n-butyl)-urea 51grams of 4-methyl-3chloro-benzene-sulphamide are suspended in 80 cc. ofacetone. The suspension is mixed with 150 cc. of caustic soda solutioncontaining grams of sodium hydroxide, and, while stirring, grams ofn-butyl isocyanate are added dropwise, the temperature being maintainedat about 10 C. The reaction solution is clarified with carbon, filtered,and acidified with dilute acetic acid. A good yield of crystalline N-(4-methyl 3-chloro-benzenesulphonyl)-N'-(n-butyl )-urea is obtained. it isrecrystallised from dilute ethanol or from isopropanol. 1t melts at145-146" C.

In analogous manner there is obtained from 103 grams of2-methyl-6-chlorobenzene-sulphamide in 165 cc. of acetone and 330 cc. ofcaustic soda solution (containing 20 grams of sodium hydroxide) byreaction with grams of n-butyl isocyanate,N-(2-methyl-6-chl0robenzenesulphonyl) -N-(n-butyl)-urea melting at 154-155 C.

3.1 grams of the N(4-methyl-3-chloro-benzenesulphonyl)-N'-(n-butyl)-urea are dissolved,while h ating, in an equivalent quantity of 1 N-sodium hydroxidesolution (about 10 cc.). On cooling, the sodium salt of N-(4- methyl3-chloro-benzenesulphonyl)-N'-n-butyl-urca separates. After drying for 1day it melts above 165 C. The sodium salt is easily soluble in warmwater but rather ditficultly soluble in cold water. The solutions show apH-value of 8-9.

Example 8.N-(4-methyl-3-chloro-benzenesulphonyl) -N'-isobutyl'urea (a) Asuspension of 64 grams of 4-methyl-3-chlorobenzenesulpharnide, 120 gramsof potassium carbonate and 600 cc. of acetone is heated, while stirring,for 1 hour at C. 37.6 grams of ethyl chlorocarbonate are then slowlyadded dropwise, and the whole is stirred for 4 hours at 55 C. Aftercooling the mixture, the precipitate is filtered off with suction anddissolved in 500 cc. of water. The filtrate is clarified with animalcharcoal and acidified with hydrochloric acid to precipitate 4-methyl-3-chlorobenzenesulphonyl-carbamic acid ethyl ester in the form of asmeary mass which soon crystallises throughout. The resulting4-methyl-3-chloro-benzenesulphonyl-carbamic acid ethyl ester is filteredoff with suetion and washed with water. The product melts at 85- 87" C.

(b) 55.5 grams of the resulting dried 4-methy1-3-chloro-benzenesulphonyl-carbamic acid ethyl ester are refluxed at theboil for 4 hours with 16 grams of isobutylamine in 107 grams of glycolmonomethyl ether. The mixture is then evaporated under reduced pressure.The warm residue is dissolved in dilute ammonia solution. The solutionso obtained is clarified with animal charcoal and a small quantity of4-methyl-3-chloro-benzene-sulphamide is removed. Acidification of thefiltrate with dilute hydrochloric acid produces a crystallineprecipitate of N-(4- methyl 3 chloro benzenesulphonyl)-N'isobutyl-urea,which is filtered ofi with suction and recrystallised from aqueousethanol of percent strength. The product melts at 157-l59 C.

Example 9.-N-(4-rnethoxy-3-chloro-benzenesulphonyl)- N -allyl-urea 20grams of N (4 methoxy 3 chloro-benzene-sulphonyl)-carbamic acid methylester melting at 142-144 C. (prepared by reacting4-methoxy-3-chloro-benzenesulphamide with chloroformic acid methyl esterin the presence of anhydrous potassium carbonate), grams of1.2-dichlor-benzene and 4.6 grams of allylamine are heated for 7 /2hours at C. The reaction mixture is cooled and extracted twice with 0.5N-sodium hydroxide solution. The combined alkaline solutions are treatedfor clarification with animal charcoal and are then slowly acidifiedwith 2 N-hydrochloric acid. The precipitate is filtered ed with suction,taken up in about cc. of dilute ammonia (1 :25), the undissolved matteris filtered off and the sulphonyl-urea is precipitated by acidifyingwith 2 N-hydrochloric acid. After recrystallisation from about 110 cc.of ethanol of 60 percent strength, the N-(4-methoxy-3-chloro-benzenesul'phony)-N-allyl-urea is obtained in a goodyield. It melts at 143-144 C.

Example l0.-N-(4-chloro-benzenesulphonyl)-N'-hexyll -urea 25 grams ofpara-chloro-benzene-sulphamide are dissolved in 200 cc. of acetone, 50grams of powdered potassium carbonate are added and, while stirring at40 C., 18 grams of n-hexylisocyanate are slowly added dropwise. Thereaction mixture is refluxed for 3 hours and the acetone is thendistilled off. The residue is dissolved in dilute ammonia, the solutionis clarified with animal charcoal and reacidified with hydrochloricacid. The N- (4-chloro-benzenesulphonyl)-N'-hexyl-(1)-urea obtained in agood yield is filtered off with suction, washed well with water and,after drying, recrystallized from acetonitrile. It melts at 115 C.

Example 11.N- 3-chloro-4-methyl-benzenesulphonyl) N-ethyl-urea 28 gramsof 3 chloro 4 methyl benzenesulphonylethylurethane (prepared by reacting3-chloro-4-methylbenzene-sulphamide and chloroformic acid ethyl ester inacetone in the presence of potassium carbonate) are dissolved in 40 cc.of a solution of 20 percent strength of ethylamine in benzene. Thebenzene and the ethylamine in excess are distilled off and the residueis heated for 2 hours at 130 C. in the oil bath. After cooling, theresidue is dissolved in dilute ammonia, the solution is clarified withanimal charcoal and cautiously acidified in the heat with hydrochloricacid. After cooling, the N-(3-chloro-4-methy1-benzene-sulphonyl)-N-ethyl-urea which has precipitatedin a good yield is filtered oif with suction and washed with water.After drying and recrystallizing from acetonitrile, the substance meltsat 137-138" C.

We claim:

1. Compounds selected from the group consisting of (1) benzenesulphonylureas of the formula R wherein R is chlorine and R is alkyl of 2 to 7carbon atoms.

3. The compound of the formula 4. The compound of the formula 5. Thecompound of the formula 6. The compound of the formula 7. The compoundof the formula 8. Benzenesulphonylureas of the formula Q-SOr-NH-CO-NH-Rz01 wherein R is alkyl of 2 to 7 carbon atoms.

10 9. Benzenesulphonylureas of the formula -S O 2NH- C O NHC 4H0 01 10.The compound of the formula CH: Cl

11. The compound of the formula 12. The compound of the formulaReferences Cited UNITED STATES PATENTS 2,336,907 12/1943 Winnek 2605532,371,178 3/1945 Martin et al. 260553 2,390,253 12/1945 Henke 2605532,411,661 11/1946 Martin et al. 260553 2,813,902 11/1957 Margot et al260553 2,891,960 6/1959 Ruschig et al. 260553 2,975,212 3/1961 Wagner etal. 260553 2,804,422 8/1957 Schumann et al 16765 2,902,404 9/1959Spencer 167-65 2,928,871 3/1960 Aeschlimann et al. 260553 2,962,53011/1960 Habicht 260553 3,211,615 10/ 1965 McLamore.

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Portuguese Patent 33,014 in Appendix to Diario da Governo: Boletim daPropriedade Industrial, No. 4, pp. 329-330, 1956.

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Degering, An Outline of Organic Chemistry, 6th ed., pp. 25-26, 30-31 and171, Barnes and Noble, Inc. (N .Y.), 1951.

JOHN D. RANDOLPH, Primary Examiner.

H. J. LIDOFF, IRVING MARCUS, WALTER A.

MODANCE, Examiners.

E. E. BERG, E. K. MERKER, Assistant Examiners.

1. COMPOUNDS SELECTED FROM THE GROUP CONSISTING OF (U) BENZENESULPHONYLUREAS OF THE FORMUAL